Alveolar Capillary Dysplasia

Synonyms of Alveolar Capillary Dysplasia

ACD

General Discussion

Alveolar capillary dysplasia (ACD) is a rare, likely congenital, disorder of the lungs (pulmonary system) and especially of the blood system serving the lungs. It is a disorder of the newborn. The normal diffusion process of oxygen from the air sacs to the blood in the lungs and, thence, to the heart, fails to develop properly. The disorder is sometimes called misalignment of the pulmonary veins. Rather than misaligned, the pulmonary vein is malpositioned in a site somewhat different from its normal position.

Infants with the disorder present with the signs of lack of oxygen (hypoxemia) and severely increased pulmonary hypertension.

Since treatment is seldom, if ever, effective, life expectancy of the infant is very, very, short.

Signs & Symptoms

Infants, most often in the first few days of life, present with the signs of a lack of oxygen (cyanosis) and high blood pressure in the pulmonary artery (neonatal pulmonary hypertension). Many patients will also show signs of cardiac anomalies, and/or systemic abnormalities of the urinary or gastrointestinal tract.

The disorder is noted for its superficial resemblance to idiopathic persistent pulmonary hypertension of the newborn (PPHN) with which ACD may be confused. In contrast to infants with PPHN, those with ACD do not respond to heroic efforts such as mechanical ventilation, nitric oxide, and extra corporeal membrane oxygenation (ECMO). ECMO is a special procedure that uses an artificial heart-lung machine to take over the work of the lungs (and sometimes also the heart). This procedure is used most often in newborns and young children, but it also can be used as a last resort for adults whose heart or lungs are failing.

ACD may be accompanied by other systemic symptoms, such as disorders of the eye and heart, and may even mimic the genetic disorder trisomy 21.

Causes

For reasons that are unclear, the capillaries and small veins of the emerging lungs fail to develop properly before birth. While in the womb, immature veins (venous channels) arise located, inappropriately, in what is called the bronchovascular bundle. These immature veins attach themselves to the pulmonary veins that are in their typical locations. This is the origin of the idea of misaligned pulmonary veins. This process was made clear by studies of the cells of the lungs (histological) of very young or premature infants.

The cause(s) of ACD is (are) not known although at least one-half a dozen cases among family members (siblings) have been reported. Based on these observations, and other evidence, some clinicians believe that there may be a genetic component to ACD that is not fully understood. Despite intensive searching, the faulty gene has not been identified and thus the location of this faulty gene remains unknown. Clinicians believe that the genetic trait involved is most likely transmitted as an autosomal recessive trait.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13″ refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are located on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

As of 1997, there were about 50 cases of alveolar capillary dysplasia reported. There are certainly many more now. The disorder appears to affect infants born at full term, and affects girls and boys equally.

Related Disorders

Symptoms of the following disorders can be similar to those of alveolar capillary dysplasia. Comparisons may be useful for a differential diagnosis.

Idiopathic Persistent Pulmonary Hypertension

Idiopathic persistent pulmonary hypertension of the newborn (PPHN) is characterized by markedly high blood pressure in the pulmonary artery (pulmonary hypertension) of infants that, in turn, causes blood to bypass its normal route and results in less oxygen than required being delivered to the lungs (hypoxemia). PPHN may occur without known cause (idiopathically), or it may arise in connection with many different neonatal cardiorespiratory disorders, including asphyxia, meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), and congenital diaphragmatic hernia.

During fetal life, pulmonary blood flow is low, with less than 10% of the combined cardiac output directed to the lungs. Following birth, pulmonary vascular resistance falls dramatically as the lungs assume the function of gas exchange. In some newborn infants, the normal decrease in pulmonary vascular tone does not occur, resulting in persistent pulmonary hypertension of the newborn (PPHN). This syndrome results in substantial morbidity and mortality in otherwise healthy term infants.

Most infants with PPHN respond to therapies such as inhaled nitric oxide and extracorporeal membrane oxygenation. Most (~90%) recover by the second week of life and survive.

Surfactant Protein B Deficiency

Surfactant protein B deficiency is a congenital (present at birth and associated with a gene defect) disorder; of the lungs that occurs primarily in infants born prematurely and is a result of immaturity of the lungs. The mature lung contains a foamy fluid known as surfactant, a substance essential to expansion of the alveoli or air sacs of the lungs. Because of their immaturity, premature babies tend to lack surfactant. Without surfactant, the lungs cannot inflate, resulting in RDS.

Pulmonary surfactant is a complex compound composed primarily of fatty substances and lesser amounts of cholesterol and surfactant-associated protein. When the protein component is missing, the surfactant cannot function properly. The surfactant, when functioning properly, lowers surface tension at the air-liquid interface in the alveoli of the lung, permitting the exchange of oxygen.

Pulmonary Hypoplasia

Pulmonary hypoplasia is a malformation characterized by incomplete development of lung tissue. Defining pulmonary hypoplasia is difficult, but some investigators have devised specific criteria that are based on reduced lung weight, volume, DNA content, and radial alveolar count. The causes (etiologies) in order of frequency are prolonged rupture of membranes prior to birth, kidney disease leading to low urine output in the fetus, and fetal neuromuscular diseases. In cases of premature rupture of membranes at 15-28 weeks’ gestation, the reported incidence of pulmonary hypotension is 9-28%.

Pulmonary hypoplasia is frequently accompanied by severe pulmonary hypertension. In many cases, it may only be differentiated from ACD through direct examination of lung tissue.

Diagnosis

Alveolar capillary dysplasia may be suspected in any infant who presents with severe cyanosis (hypoxemia) and high pulmonary blood pressure (pulmonary hypertension) that is unresponsive to treatment in the neonatal intensive care unit (NICU). The diagnosis is confirmed through an examination of lung tissue by an experienced pathologist for characteristic cellular changes. The characteristics that a pathologist will look for include, according to one expert, a relative lack of capillaries near the alveoli, thickening of the walls (septa) of alveoli, and increased “muscularization” of the small arteries of the lungs (arterioles).

Standard Therapies

Treatment

None of the many treatment modes that are used to treat pulmonary hypertension have resulted in prolonging life expectancy or long-term survival. The methods tried include mechanical ventilation, inhaling high concentrations of oxygen, inhaled nitric oxide, and ECMO (extracorporeal membrane oxygenation).

Investigational Therapies

A number of clinical trials involving inhaled nitric oxide have proven effective for the treatment of neonatal pulmonary disorders such as idiopathic persistent pulmonary hypertension. None have been effective in treating ACD. There has been talk about trying lung transplantation but progress in this direction has been held up because of the scarcity of donor lung tissue.

Investigators at the Baylor College of Medicine, working with the support of the Alveolar Capillary Dysplasia Association, are engaged in efforts to identify the faulty gene responsible for ACD.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

Merchak A, Lueder GT, White FV, et al. Alveolar capillary dysplasia with misalignment of pulmonary veins and anterior segment dysgenesis of the eye: a report of a new association and review of the literature. J Perinatol. 2001;21:327-30.

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